Efficient synthesis of 1,4,7-triazacyclononane and 1,4,7-triazacyclononane-based bifunctional chelators for bioconjugation

Article abstract of DOI:10.1002/ejoc.201402708

The reaction of diethylenetriamine with chloroacetaldehyde yielded a bicyclic aminal intermediate for the synthesis of 1,4,7-triazacyclononane (TACN), a macrocyclic polyamine the derivatives of which find applications as catalysts, bleaching agents, and chelators for medical imaging. This new synthetic protocol outperforms the synthetic methods described so far because it does not involve any cyclization step. Moreover, this aminal intermediate allowed access to a new family of TACN derivatives functionalized on the carbon skeleton, for example, C-aminomethyl-TACN. This novel compound is a precursor of valuable bifunctional chelating agents for nuclear medicine, in particular, for the preparation of PET imaging agents after bioconjugation and metallation with ⁶⁸Ga or ⁶⁴Cu.

Full text of DOI:10.1002/ejoc.201402708

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DOI: 10.1002/ejoc.201402708
Efficient Synthesis of 1,4,7-Triazacyclononane and 1,4,7-Triazacyclononane-
Based Bifunctional Chelators for Bioconjugation
Pauline Désogère,[a] Yoann Rousselin,[a] Sophie Poty,[a] Claire Bernhard,[a] Christine Goze,[a]
Frédéric Boschetti,[b] and Franck Denat*[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Amines / Macrocyclic polyamines / Chelates
The reaction of diethylenetriamine with chloroacetaldehyde
yielded a bicyclic aminal intermediate for the synthesis of
1,4,7-triazacyclononane (TACN), a macrocyclic polyamine
the derivatives of which find applications as catalysts,
bleaching agents, and chelators for medical imaging. This
new synthetic protocol outperforms the synthetic methods
described so far because it does not involve any cyclization
step. Moreover, this aminal intermediate allowed access to a
new family of TACN derivatives functionalized on the carbon
skeleton, for example, C-aminomethyl-TACN. This novel
compound is a precursor of valuable bifunctional chelating
agents for nuclear medicine, in particular, for the preparation
of PET imaging agents after bioconjugation and metallation
with 68Ga or 64Cu.
cine, particularly in the development of radiopharmaceuti-
cals for diagnosis (imaging) and therapy (radioimmunother-
apy).[10] Indeed, TACN derivatives provide versatile plat-
forms for obtaining efficient bifunctional chelating agents
(BFCA) capable of strongly coordinating a radio-metal
(such as 111In, 67/68Ga, 64/67Cu, and 90Y for SPECT, PET
imaging, or radiotherapy applications) and ensuring the at-
tachment of the targeting vector. TACN is also an efficient
chelator for the preparation of 99mTc radiopharmaceuti-
cals.[10e] Derivatives bearing additional coordinating groups,
such as carboxylates[11] and phosphinates,[12] have been par-
ticularly used in the development of BFCAs with optimal
properties for CuII and GaII chelation.
Despite the interest in TACN derivatives, only a few syn-
thetic methodologies have been reported in the literature.
The only reported synthesis of TACN follows the general
procedure for the preparation of macrocyclic polyamines
developed by Richman and Atkins 40 years ago.[13] How-
ever, this method suffers from many drawbacks, for exam-
ple, the use of tosyl groups to preorganize the intermediates
to favor intramolecular cyclization is not atom-economic.
Moreover, the method requires long reaction times and al-
though the macrocyclization step is generally efficient,
harsh conditions are required to remove the tosyl groups.
The method has also been extended to the synthesis of C-
functionalized TACN derivatives by using bis-electrophilic
synthons that are functionalized on a carbon atom.[14] Such
C-functionalized macrocycles are of special interest for the
synthesis of BFCAs because the targeted biomolecule can
be attached to a carbon atom of the TACN derivative with
the three nitrogen atoms remaining available for further
functionalization with coordinating arms. This approach,
however, requires the preparation of a sophisticated C-func-
tionalized precursor that must be resistant to the deprotec-
Introduction
The interest in the synthesis of 1,4,7-triazacyclononane
(TACN) and its derivatives has increased due to the use of
their metal complexes in a wide range of applications, from
catalysis to molecular imaging. This class of compounds
has appeared in more than 300 patents in 30 years. Numer-
ous metal complexes have been prepared, including MnII–V
,
FeII, FeIII, RuII–IV and RuVI, CoIII, GaIII, CuII, and ZnII.[1]
The ability of triazacyclononane derivatives to stabilize
high oxidation states of metal ions, in particular manganese,
has led to the development of such complexes as oxidation
catalysts. In particular, the ligand 1,4,7-trimethyl-1,4,7-tri-
azacyclononane (MeTACN) has been the subject of many
studies because of the catalytic activity of its binuclear
manganese tris-oxo complex [(MeTACN)2Mn2O3]2+ [2]
.
MeTACN–MnIV complexes have been used as bleaching
agents in laundry formulations[2b] and as catalysts in olefin
polymerization[3] and olefin epoxidation with hydrogen per-
oxide in water[4] or organic solvents[5] as well as in other
oxidation processes.[6] Protein orientation at interfaces,[7]
metalloenzyme biosite models,[8] and magnetic molecule
clusters[9] are other examples of domains in which TACN
derivatives have been exploited.
The interest in these macrocyclic molecules has contin-
ued to grow in the past 10 years in the field of nuclear medi-
[a] Institut de Chimie Moléculaire de l’Université de Bourgogne,
UMR CNRS 6302,
9 Avenue Alain Savary, 21000 Dijon, France
E-mail: franck.denat@u-bourgogne.fr
http://icmub.fr/
[b] CheMatech,
9 Avenue Alain Savary, 21000 Dijon, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402708.
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Figure 1. Retrosynthetic scheme for TACN and its N- and C-functionalized derivatives.
tion conditions. A method allowing functionalization of a philic agent, undergoing ring-opening and resulting in the
carbon atom starting from MeTACN and involving a bi- formation of compound 2 in 37% yield after recrystalli-
cyclic pyrazinium salt as key intermediate has been reported zation in water.
in the literature,[15] however, this method requires the pre-
The structure of 2 in its doubly protonated form was
liminary synthesis of MeTACN by the method of Richman confirmed by X-ray diffraction (Figure 2). Compound 2
and Atkins and is limited to the synthesis of C-function- crystallizes with two chloride anions and three water mol-
alized MeTACN.
ecules. The protons on the macrocycle were located in the
Inspired by the previous work, a new methodology using Fourier difference map. The distances C2–N2, C3–N2, and
the “aminal tool” has been developed in our group to easily C14–N2 [1.474(3), 1.467(3), and 1.482(3) Å, respectively]
synthesize TACN and its N- and C-functionalized deriva- are shorter than those of protonated nitrogen atoms [C1–
tives. The process involves three different steps: 1) The syn- N1 1.512(3) Å, C6–N1 1.516(3) Å, C7–N1 1.535(3) Å, C5–
thesis of an aminal intermediate from the commercially N3 1.506(3) Å, C4–N3 1.504(3) Å, C21–N3 1.519(3) Å],
available linear diethylenetriamine, 2) functionalization of which is in agreement with the protonation scheme.
the secondary amines and quaternization of the tertiary
Finally, the benzyl groups of 2 were cleaved by
amine of the aminal with a suitable electrophilic reagent, hydrogenolysis to give TACN 3 in 95% yield after
and 3) double-ring-opening by nucleophilic attack (Fig- recrystallization. The process reported herein is very ef-
ure 1).
ficient and reproducible. It gives access to TACN in three
steps from the commercially available linear diethylenetri-
amine in 25% overall yield. Moreover, no tedious chroma-
tographic work-up was necessary, all the compounds being
Results and Discussion
The aminal intermediate 1 was easily obtained by ad- isolated by recrystallization. This new synthetic procedure
dition of chloroacetaldehyde to diethylenetriamine in the outperforms the approach described so far, it can be easily
presence of potassium carbonate (Scheme 1). Next, 3 equiv. scaled up (see Exp. Sect.), and it has been patented.[16]
of benzyl bromide were added to compound 1 to yield the
This reaction can also be used for the preparation of N-
expected ammonium salt, which was not isolated. The am- functionalized TACN by using the desired electrophilic rea-
monium salt was treated with NaBH4 as a hydride nucleo- gent for the synthesis of the ammonium salt. For example,
Scheme 1. Synthesis of TACN and N-functionalized TACN. Reagents and conditions: (a) 2 equiv. K2CO3, CH3CN, room temp.;
(b) 3 equiv. BnBr, 4 equiv. K2CO3, CH3CN, 10 °C, 24 h; (c) 1 equiv. NaBH4, EtOH, –10 °C, 12 h; (d) H2, Pd/C, CH3CO2H, room temp.,
3 d; (e) 3 equiv. 2-(bromomethyl)pyridine hydrobromide, 10 equiv. K2CO3, CH3CN, 10 °C, 12 h; (f) 1 equiv. NaBH4, EtOH, –10 °C, 12 h.
2
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Triazacyclononane-Based Bifunctional Chelators
Derivatives 6 and 7 were recrystallized and their struc-
tures elucidated by X-ray diffraction (Figures 3 and 4).
Compound 6 is triprotonated and the protons were located
in the Fourier difference maps on primary amine N4 and
the two tertiary amines N1 and N3. The structure has four
counter anions, and the compound crystallizes with a
hydronium cation (O2) and one water molecule (O1). The
protonation scheme of the macrocycle is also supported by
the distances C2–N2, C3–N2, and C14–N2 [1.469(3),
1.469(3), and 1.474(3) Å, respectively], shorter than the am-
monium C–N distance [C1–N1 1.505(3) Å, C6–N1
1.510(3) Å, C7–N1 1.521(3) Å, C4–N3 1.510(3) Å, C5–N3
Figure 2. OLEX2[17] view of compound 2. Thermal ellipsoids are
drawn at the 50% probability level. Hydrogen bonds are shown as
dashed lines.
the addition of 3 equiv. of a pyridine derivative instead of
benzyl bromide gives access to compound 4 in three steps
starting from the linear amine without the need for a pro-
tection/deprotection step (Scheme 1).
We then investigated the synthesis of new C-function-
alized TACN derivatives. Thus, the addition of sodium
cyanide to the quaternized ammonium salt yielded com-
pound 5 in 63% yield (Scheme 2). The nitrile was reduced
with LiAlH4 and the benzyl groups then removed by
hydrogenolysis to give the C-aminomethylTACN 7.
Figure 3. OLEX2[17] view of compound 6. Thermal ellipsoids are
drawn at the 50% probability level. Hydrogen bonds are shown as
dashed lines.
Scheme 2. Synthesis of C-aminomethylTACN. Reagents and condi-
tions: (a) 3 equiv. BnBr, 4 equiv. K2CO3, CH3CN, 10 °C, 6 h;
(b) 1 equiv. NaCN, room temp., 3 d; (c) 1.1 equiv. LiAlH4, THF, Figure 4. OLEX2[17] view of compound 7. Thermal ellipsoids are
–78 °C, 12 h; (d) H2, Pd/C, CH3CO2H/H2O/THF, room temp.,
10 d.
drawn at the 50% probability level. Hydrogen bonds are shown as
dashed lines.
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1.511(3) Å, C21–N3 1.522(3) Å]. Compound 7, which crys- prior to functionalization of the primary amine for further
tallizes with four chloride anions and one water molecule, bioconjugation.
was obtained in its fully protonated form. The protons on
The three amines of the TACN ring of new precursor 9
the amine were also located in the Fourier difference maps. were functionalized, followed by removal of the Boc pro-
The protected and non-protected C-aminomethylTACNs tecting group (Scheme 3). Compound 10 was obtained by
6 and 7, respectively, represent highly valuable building addition of 3 equiv. of tert-butyl bromoacetate followed by
blocks for the preparation of BFCAs. As a result of the cleavage of all the protecting groups to give compound 11
powerful method described in this paper, a wide range of (MA-NOTA). This method is highly versatile because any
new promising BFCAs can be generated from these precur- kind of grafting function can be introduced onto the pri-
sors by functionalization of the secondary and/or primary mary amine in the last step. To demonstrate the potential
amino groups. To introduce various grafting functions, we use of compound 11 as a precursor of a new BFCA, we
used a protection/deprotection sequence starting from the prepared a “ready-to-be-grafted” NOTA chelator, the so-
synthon 6 (Scheme 3). The addition of 1 equiv. of Boc2O called p-NCS-Bz-MA-NOTA (14). A pendant arm bearing
to 6 followed by selective removal of the benzyl group by a nitro functional group was easily introduced by using an
hydrogenolysis gave access to compound 9 in good yield. activated ester precursor leading to compound 12. The re-
Such a strategy allows discrimination between primary and action was performed in a mixture of solvent (CH3CN/
secondary nitrogen atoms and enables the introduction of water) to overcome solubility problems. After reduction of
various pendant coordinating arms for metal chelation the nitro group by hydrogenolysis, the desired isothio-
cyanate function was introduced by the addition of thio-
phosgene.
Bearing in mind that compound 7 could also be modified
without protection/deprotection steps, we investigated the
reaction of 7 with aldehydes. Inspired by our previous work
that revealed the versatility of using aldehyde to introduce
a functional group selectively onto the amino pendant
group of 13aneN4 derivatives,[18] we decided to explore this
reaction by treating 7 with 1 equiv. of an aldehyde bearing
an alkyne function. Treatment of the precursor 7 with 4-
(prop-2-ynyloxy)benzaldehyde followed by reduction with
NaBH4 resulted in the formation of compound 15 in 68%
yield (Scheme 4). Further functionalization of the second-
ary amines with coordinating arms will give access to new
TACN-based BFCAs for site-specific bioconjugation using
click chemistry.[19] Note that if the reaction of an aldehyde
with 7 is selective towards the primary amine, the reaction
with an activated carboxylic acid resulted in a mixture of
products that we were not able to separate. In this case, an
alternative synthetic strategy using intermediate 11 must be
used.
Scheme 4. Synthesis of TACN precursor 15 for click chemistry.
Reagents and conditions: (a) 4-(Prop-2-ynyloxy)benzaldehyde,
EtOH, room temp., 48 h, 10 equiv. NaBH4, EtOH, room temp.,
12 h.
Scheme 3. Synthesis of the bifunctional chelating agents MA-
NOTA and p-NCS-Bz-MA-NOTA. Reagents and conditions:
(a) 1 equiv. Boc2O, DCM, room temp., 12 h; (b) H2, Pd/C,
Conclusions
CH3CO2H/H2O/THF, room temp., 2 d; (c) 3 equiv. tert-butyl
bromoacetate, 7 equiv. K2CO3, DMF, 40 °C, 24 h; (d) TFA/
synthesis of TACN and N-functionalized TACNs via the
CH2Cl2, room temp., 24 h; (e) N-succinimidyl 4-nitrophenylacetate,
DIPEA, CH3CN, room temp., 2 h; (f) H2, 10% Pd/C, 1 d; (g) thio-
phosgene, CH2Cl2/H2O, 3 h, room temp.
We have developed a new powerful methodology for the
key formation of an ammonium salt intermediate. The
strategy was also used for the preparation of C-function-
4
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Triazacyclononane-Based Bifunctional Chelators
(6 CH2-α) ppm. MS (MALDI-TOF): m/z = 400 [M]+. HRMS
(ESI): calcd. for C27H33N3 + H+ 400.2747 [M + H]+; found
400.2733. C27H33N3·3HCl·1.5H2O (534.21): calcd. C 60.50, H 7.33,
N 7.84; found C 60.39, H 7.87, N 8.04.
alized derivatives, providing valuable building blocks for the
synthesis of new BFCAs. Indeed, the use of suitable func-
tionalization sequences allowed the selective introduction of
coordinating pendant arms for metal chelation and grafting
functions for bioconjugation. The chelator p-NCS-Bz-MA-
NOTA bearing the isothiocyanate function is currently be-
ing used in our laboratory to label antibodies for immuno-
PET applications. The extension of the method for the
preparation of new BFCAs that contain other functional
groups, such as maleimide or the thioctic moiety, which are
suitable for attachment to cysteine or gold nanoparticles,
respectively, is underway. Finally, the incorporation of a
fluorescent dye will also give rise to a new class of SPECT
or PET/optical probes for bimodal imaging applications.
1,4,7-Triazacyclononane (3): Compound 2 (84.77 g, 0.21 mol) was
placed in acetic acid (1 L) with 10% Pd/C (9 g, 8 mmol, 0.04 equiv.)
under H2. After consumption of hydrogen (14.3 L, 0.63 mol,
3 equiv.), the solvent was removed. Hydrochloric acid (37%,
52 mL) and then ethanol (250 mL) were added. The precipitate
thus formed was filtered, the white solid was washed with diethyl
ether (200 mL), and compound 3 was obtained as a white solid
(26 g, 0.20 mol, 95%). 1H NMR (300 MHz, CDCl3, 298 K): δ =
2.75 (s, 12 H), 2.07 (s, 3 H, NH) ppm. 13C NMR (75 MHz, CDCl3,
298 K): δ = 42.4 (CH2-α) ppm. MS (MALDI-TOF): m/z = 129.70
[M]+. HRMS (ESI): calcd. for C6H13N3 + H+ 130.1338 [M + H]+;
found 130.1332.
1,4,7-Tris(pyridin-2-ylmethyl)-1,4,7-triazacyclononane
(4):
2-
Experimental Section
(Bromomethyl)pyridine hydrobromide (9.85 g, 39.0 mmol, 3 equiv.)
was slowly added at 10 °C to a solution of 1 (1.62 g, 13.0 mmol)
and K2CO3 (45.5 g, 330.0 mmol) in acetonitrile (90 mL). The mix-
ture was stirred at room temperature overnight. After filtration
through Celite, the solvent was removed. The oily residue was taken
up overnight in diethyl ether (200 mL) and the resulting precipitate
was filtered, washed with diethyl ether (2ϫ 20 mL), and dried in
vacuo to give 12.96 g of the intermediate. The intermediate (5.0 g,
10.3 mmol) was then placed in dry ethanol (45 mL) and NaBH4
(3.9 g, 103.0 mmol) was added at –10 °C to the solution. After 12 h,
the solvent was evaporated in vacuo and the resulting mixture
taken up in diethyl ether (50 mL). Insoluble impurities were re-
moved by filtration. After evaporation of the solvent, compound 4
was obtained as an orange oil (1.62 g, 31%). 13C NMR (75 MHz,
CDCl3, 298 K): δ = 150.3 (3 C), 145.6 (3 C), 143.5 (3 C), 127.3 (3
C), 126.4 (3 C), 56.3 (3 C), 49.3 (6 C) ppm. MS (ESI): m/z = 403.26
[M + H]+. HRMS (ESI): calcd. for C24H30N6 + H+ 403.2605 [M
+ H]+; found 403.2594.
General: All chemicals were purchased from Acros and Aldrich and
used without further purification. The precursor 3-(prop-2-ynyl-
oxy)benzaldehyde was prepared as described in the literature.[20]
Organic solvents were removed under reduced pressure by using a
rotary evaporator. Water was removed from the products by lyophi-
lization.
Octahydroimidazo[1,2-a]pyrazine (1): A solution of chloroacetalde-
hyde (50% in water, 111.8 g, 0.71 mol) in acetonitrile (500 mL) was
added at 20 °C to
a solution of diethylenetriamine (73.3 g,
0.71 mol) and K2CO3 (196.8 g, 1.42 mol, 2 equiv.) in acetonitrile
(1 L). The mixture was stirred at this temperature for 6 h. After
filtration through Celite, the solvent was evaporated. The oily resi-
due was taken up in diethyl ether (800 mL) and insoluble impurities
were removed by filtration. After evaporation of the solvent, com-
pound 1 was isolated as a yellow oil (64.3 g, 71%). 1H NMR
2
3
(300 MHz, CDCl3, 298 K): δ = 3.15 (dd, JH,H = 11.6, JH,H
=
2.7 Hz, 1 H, CH2CH), 3.06–2.96 (m, 2 H), 2.92–2.67 (m, 5 H), 2.48
2
3
1,4,7-Tribenzyl-1,4,7-triazacyclononane-2-carbonitrile (5): Benzyl
bromide (259.3 g, 1.5 mol) was slowly added to a solution of 1
(64.3 g, 0.5 mol) and K2CO3 (278.8 g, 2.0 mol) in acetonitrile
(1.1 L) at 10 °C and the resulting solution was stirred for 6 h. Then
sodium cyanide (24.76 g, 0.5 mol) was carefully added and the mix-
ture was stirred at room temperature for 3 d. After filtration
through Celite, the solvent was evaporated in vacuo and the resid-
ual oil was taken up in diethyl ether (3 L). Insoluble impurities were
removed by filtration. After evaporation of the solvent, compound
5 was obtained as a brown oil (137.2 g, 63%). 1H NMR (300 MHz,
CDCl3, 298 K): δ = 7.40–7.16 (m, 15 H), 3.84–3.63 (m, 6 H), 3.53–
3.42 (m, 1 H), 3.22–3.14 (m, 1 H), 2.99–2.95 (m, 1 H), 2.88–2.82
(m, 2 H), 2.74–2.66 (m, 1 H), 2.56–2.43 (m, 4 H), 1.78–1.53 (m, 1
H) ppm. 13C NMR (75 MHz, CDCl3, 298 K): δ = 140.0 (Car),
139.9, 139.4, 138.4, 129.5 (CHar), 129.2, 129.1 (2 C), 128.9, 128.7,
128.5, 128.4, 128.3, 128.2, 127.8, 127.2, 127.1, 126.9, 118.1 (CN),
66.1 (CH2), 63.6, 62.3, 61.5, 58.9, 57.5, 56.5, 55.6, 54.8 (CH) ppm.
(dd, JH,H = 11.6, JH,H = 8.0 Hz, 1 H, CH2CH), 2.28–2.15 (m, 2
H), 1.72–1.62 (br. s, 2 H, NH) ppm. 13C NMR (75 MHz, CDCl3,
298 K): δ = 75.9 (CH), 51.7 (CH2α), 50.4, 48.6, 44.5, 42.2 ppm.
1,4,7-Tribenzyl-1,4,7-triazacyclononane (2): Benzyl bromide
(353.97 g, 2.06 mol, 3 equiv.) was slowly added at 10 °C to a solu-
tion of 1 (87.61 g, 0.69 mol) and potassium carbonate (380 g,
2.76 mol, 4 equiv.) in acetonitrile (1.8 L). The mixture was stirred
at room temperature overnight. After filtration through Celite, the
solvent was removed. The product was then placed in ethanol
(1.8 L) and sodium borohydride (26 g, 0.69 mol, 1 equiv) was
added at –10 °C to the solution. After 12 h, the solvent was re-
moved, the resulting mixture was taken up in chloroform (1.5 L),
and insoluble salts were removed by filtration through Celite. After
evaporation of the solvent, the residual oil was taken up in diethyl
ether (1.5 L), and insoluble products were removed by filtration.
The solvent was evaporated, the residual brown oil was placed in
ethanol (200 mL), and hydrochloric acid (37%, 100 mL) was
added. After evaporation of the solvent, acetone (500 mL) was
added and the white precipitate thus formed was filtered and
recrystallized from water (400 mL). The crystals were filtered and
deprotonated with a 13 m NaOH solution until pH Ͼ 12. After
extraction with chloroform, the organic phase was dried with
MgSO4. After filtration and evaporation of the solvent, compound
2 was obtained as a colorless oil (102 g, 0.255 mol, 37%). 1H NMR
IR: ν = 2250 (CN) cm–1. MS (ESI): m/z = 425.25 [M + H]+. HRMS
˜
(ESI): calcd. for C28H32N4 + H+ 425.2700 [M + H]+; found
425.2694.
(1,4,7-Tribenzyl-1,4,7-triazacyclononan-2-yl)methanamine (6):
A
solution of 5 (112.7 g, 0.27 mol) in THF (450 mL) was slowly
added at –78 °C to a suspension of LiAlH4 (11.5 g, 0.32 mol,
1.2 equiv.) in THF (450 mL) under nitrogen. An emission of fumes
(300 MHz, CDCl3, 298 K): δ = 7.45–7.28 (m, 15 H), 3.70 (s, 6 H), was observed. The resulting mixture was stirred overnight and
2.91 (s, 12 H) ppm. 13C NMR (75 MHz, CDCl3, 298 K): δ = 140.4
water (100 mL) was carefully added. After removal of the solvent,
(3 Car), 129.1 (6 C), 128.1 (6 C), 126.7 (3 CHar), 63.0 (3 CH2), 55.4 the residual green solid was taken up in chloroform (1 L), the solu-
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tion was dried with MgSO4, and insoluble impurities were removed
by filtration through Celite. The residual brown oil was placed in
acetone (200 mL) and a solution of HCl (37%, 200 mL) was care-
fully added. The white precipitate formed was filtered and recrys-
tallized from water to give 6 (·3HCl) as a white solid. The resulting
crystals were then dissolved in a 16 m NaOH solution until pH 14.
After extraction with chloroform (2ϫ 500 mL), the organic phase
was dried with MgSO4 and the solvent evaporated to give 6 as a
phase was dried with MgSO4 and the solvent evaporated to give 9
as a yellow oil (1.30 g, 80%). 1H NMR (300 MHz, CDCl3, 298 K):
δ = 5.25 (s, 1 H, NHC=O), 3.16–2.98 (m, 3 H, NH), 2.98–2.45 (m,
13 H), 1.38 (s, 9 H, CH3) ppm. 13C NMR (75 MHz, CDCl3,
298 K): δ = 156.8 (C=O), 79.5 (C), 55.4 (CH), 46.8 (CH2), 45.9,
45.6, 44.6, 44.0, 43.1, 28.6 (3 CH3) ppm. MS (ESI): m/z = 203.15
[M – tBu+2H]+, 259.15 [M + H]+. HRMS (ESI): calcd. for
C12H26N4O2 + H+ 259.2129 [M + H]+; found 259.2116.
1
yellow oil (45.3 g, 39%). H NMR (300 MHz, CDCl3, 298 K): δ =
Tri-tert-butyl
2,2Ј,2ЈЈ-(2-{[(tert-Butoxycarbonyl)amino]methyl}-
7.35–7.11 (15 H), 3.71 (br. s, 1 H), 3.62–3.21 (m, 7 H), 2.98–2.90
(m, 1 H), 2.73–2.25 (m, 10 H), 1.30 (br. s, 2 H) ppm. 13C NMR
(75 MHz, CDCl3, 298 K): δ = 141.2 (Car), 140.4, 140.2, 129.5
(CHar), 129.2, 128.8, 128.3 (C 9), 127.1, 127.0, 126.7, 64.3 (CH2),
63.5, 62.8 (CH), 58.2 (CH2), 57.9, 55.6, 55.1, 52.8, 51.1, 42.5 ppm.
MS (ESI): m/z = 429.31 [M + H]+. HRMS (ESI): calcd. for
C24H30N6 + H+ 429.3012 [M + H]+; found 429.3060.
1,4,7-triazacyclonane-1,4,7-triyl)triacetate (10): A solution of com-
pound 9 (471.1 mg, 1.84 mmol) in dimethylformamide (9.2 mL)
was heated at 40 °C. tert-Butyl bromoacetate (0.803 mL,
5.51 mmol) and potassium carbonate (1.78 g, 12.9 mmol) were
added to this solution and the reaction mixture was stirred over-
night. The suspension was filtered through a bed of Celite and the
filter cake was washed with chloroform. After evaporation of the
solvents in vacuo, the crude compound was purified by flash
chromatography on silica gel (eluent: CH2Cl2/CH3OH, 94:6) and
reversed-phase flash chromatography [eluent: (HCOOH/
H2O 0.01M)/CH3CN 60:40]. Compound 10 was obtained as a
light-yellow oil (181 mg, 18%). 1H NMR (300 MHz, CDCl3,
(1,4,7-Triazacyclononan-2-yl)methanamine (7): Compound 6 (5.0 g,
11.7 mol) was dissolved in a mixture of acetic acid (29 mL), water
(29 mL), and THF (98 mL) and then 10% Pd/C (500 mg,
0.47 mmol, 0.04 equiv.) was added under H2. After consumption
of hydrogen, the mixture was filtered to remove palladium. After
evaporation of the solvent, the residue was dissolved in ethanol
(100 mL). HCl (37%, 5 mL) was added and the resulting precipitate
was filtered after 1 h, washed with acetone (20 mL), and dried un-
der vacuum to give a white powder. The resulting precipitate was
recrystallized from water. The white crystals were dissolved in a
16 m NaOH solution until pH 14. After extraction with chloroform
(2ϫ 50 mL), the organic phase was dried with MgSO4 and the
solvent evaporated in vacuo to give 7 as a yellow oil (0.79 g, 44%).
1H NMR (300 MHz, CDCl3, 298 K): δ = 2.50–2.03 (m, 13 H),
1.95–1.75 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3, 298 K): δ =
57.1 (CH), 48.7 (CH2α), 46.4, 46.3, 46.1, 45.8, 45.5 ppm. MS (ESI):
m/z = 159.16 [M + H]+. HRMS (ESI): calcd. for C7H18N4 + H+
159.1604 [M + H]+; found 159.1597.
2
325 K): δ = 6.03 (br. s, 1 H, NHBoc), 3.79 (d, JH,H = 17.6 Hz, 1
2
2
H), 3.70 (d, JH,H = 17.6 Hz, 1 H), 3.68 (d, JH,H = 17.6 Hz, 1 H),
2
2
3.60 (d, JH,H = 17.6 Hz, 1 H), 3.43 (d, JH,H = 17.6 Hz, 1 H),
3.38–3.27 (m, 2 H), 3.26–2.64 (m, 12 H), 1.44, 1.43, 1.40, 1.39 (4 s,
36 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 298 K): δ = 171.3,
168.8, 167.3, 156.7 (NHC=OOtBu), 83.1 (CqtBu), 82.5, 82.1, 79.6,
56.8, 56.4, 55.9, 53.3, 51.6, 39.3 (CH2NH), 28.6 (CH3), 28.3, 28.2,
28.1 ppm. MS (ESI): m/z = 601.46 [M + H]+. HRMS (ESI): calcd.
for C30H56N4O8 + H+ 601.4171 [M + H]+; found 601.4145. HPLC
gradient: tr = 26.75 min, purity 85%.
2,2Ј,2ЈЈ-[2-(Aminomethyl)-1,4,7-triazacyclononane-1,4,7-triyl]tri-
acetic Acid (11, MA-NOTA): Trifluoroacetic acid (1 mL) was
added to a stirred solution of compound 10 (49.5 mg, 0.08 mmol)
in dichloromethane (2 mL). The resulting reaction mixture was
then stirred overnight at room temperature before it was concen-
trated in vacuo. Compound 11·3TFA was obtained as a light-yel-
low oil (54.0 mg, 100%) and directly used without purification. 1H
NMR (600 MHz, CDCl3, 325 K): δ = 4.25–3.92 (m, 3 H), 3.88–
3.53 (m, 4 H), 3.44–3.29 (m, 3 H), 3.27–3.20 (m, 2 H), 3.19–2.36
(m, 7 H) ppm. MS (ESI): m/z = 333.27 [M + H]+. HRMS (ESI):
calcd. for C13H24N4O6 + H+ 333.1769 [M + H+]; found 333.1757.
C13H24N4O63TFA: calcd. C 33.84, H 4.04, N 8.31; found C 33.64,
H 3.73, N 7.94. HPLC gradient: tr = 3.57 min, purity 86%.
tert-Butyl
[(1,4,7-Tribenzyl-1,4,7-triazacyclononan-2-yl)methyl]-
carbamate (8): A solution of Boc2O (4.20 g, 19.2 mmol) in CH2Cl2
(100 mL) was slowly added to a solution of 6 (8.24 g, 19.2 mmol)
in CH2Cl2 (150 mL). The solution was stirred overnight at room
temperature. After evaporation of the solvent, the residual oil was
purified by aluminium oxide chromatography (eluent: CH3OH/
CH2Cl2, 4:96) to give 8 as a yellow oil (7.42 g, 73%). 1H NMR
(300 MHz, CDCl3, 298 K): δ = 7.35–7.12 (m, 15 H), 5.04–4.86 (br.
s, 1 H), 4.13–3.92 (br. s, 1 H), 3.69–3.25 (m, 7 H), 3.17–2.81 (m, 3
2
3
H), 2.69–2.40 (m, 7 H), 2.34 (dd, JH,H = 13.1, JH,H = 2.1 Hz, 1
H), 1.43 (s, 9 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 298 K):
δ = 156.2 (C=O), 140.6 (Car), 140.2, 140.0, 129.4 (2 CHar), 129.1
(2 C), 128.9 (2 C), 128.3 (6 C), 127.1, 126.9, 126.8, 78.9 (C), 64.1
(CH2), 63.7, 58.5 (CH), 58.0 (CH2), 57.8, 56.1, 55.2, 53.2, 50.5,
40.6, 28.7 (3 CH3) ppm. MS (MALDI-TOF): m/z = 528.99 [M +
H]+. HRMS (ESI): calcd. for C33H44N4O2 + H+ 529.3537 [M +
H]+; found 529.3515.
2,2Ј,2ЈЈ-(2-{[2-(4-Nitrophenyl)acetamido]methyl}-1,4,7-triazacyclo-
nonane-1,4,7-triyl)triacetic Acid (12): N,N-Diisopropylethylamine
(ca. 50 μL) was added dropwise to a stirred solution of 11 (27.2 mg,
0.082 mmol) in water (2 mL) until the pH reached 9.4. The solution
was yellowish. A solution of N-succinimidyl 4-nitrophenylacetate
(22.8 mg, 0.082 mmol) in acetonitrile (1 mL) was quickly added
and the reaction mixture immediately turned red. The solution was
stirred for 2 h and the solvents evaporated in vacuo and freeze-
dried. The crude compound was dissolved in water (5 mL) and
chloroform (5 mL). The aqueous phase was washed with chloro-
form (2 ϫ 5 mL) and the organic phase was extracted with water
(5 mL). The combined aqueous layers were freeze-dried and 12 was
obtained as a light-brown powder and used directly without purifi-
cation. MS (ESI): m/z = 494.06 [M – H]–.
tert-Butyl [(1,4,7-Triazacyclononan-2-yl)methyl]carbamate (9):
Compound 8 (3.33 g, 6.30 mmol) was dissolved in a mixture of
acetic acid (20 mL), water (20 mL), and THF (60 mL) and then
10% Pd/C (266 mg, 0.25 mmol) was added under H2. After con-
sumption of hydrogen, the mixture was filtered to remove palla-
dium. After evaporation of the solvent, the residue was dissolved
in ethanol (10 mL). A 3 m HCl solution (5 mL) was added and
the resulting precipitate filtered after 1 hour, washed with ethanol
(20 mL), and dried under vacuum to give a white powder. The re-
sulting precipitate was then dissolved in a 3 m NaOH solution until
pH 12. After extraction with chloroform (2ϫ 50 mL), the organic
2,2Ј,2ЈЈ-(2-{[2-(4-Aminophenyl)acetamido]methyl}-1,4,7-triazacyclo-
nonane-1,4,7-triyl)triacetic Acid (13): Compound 12 (40.1 mg,
0.082 mmol) was dissolved in water (1.4 mL) and 10 % Pd/C
(3.5 mg, 3ϫ10–3 mmol, 0.04 equiv.) was added under H2. The solu-
6
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Triazacyclononane-Based Bifunctional Chelators
tion was stirred vigorously and after consumption of hydrogen the
mixture was filtered through a bed of Celite to remove palladium
and the filter cake was washed with water. The crude compound
was freeze-dried and 13 was obtained as a light-yellow powder and
used directly without purification. MS (ESI): m/z = 464.09 [M –
H]–.
K
α1) = 0.71073 Å, μ = 0.812 mm–1, 6062 reflections collected, 3255
unique, minimum and maximum residual electron densities: –0.352
and 0.462 eÅ–3. For IϾ2σ(I) and all data, R(1) = 0.0327 and
0.0369, and wR(2) = 0.0705 and 0.0729, respectively.
CCDC-960359 (for 2), -960360 (for 6), and -960361 (for 7) contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
2,2Ј,2ЈЈ-(2-{[2-(4-Isothiocyanatophenyl)acetamido]methyl}-1,4,7-tri-
azacyclononane-1,4,7-triyl)triacetic Acid (14, p-NCS-Bz-MA-
NOTA): Compound 13 (38.0 mg, 0.082 mmol) was dissolved in
water (1.4 mL) and the solution stirred vigorously. Thiophosgene
(37.8 μL, 0.49 mmol) was dissolved in dichloromethane (0.45 mL)
in a test tube and the mixture was rapidly added to the previous
solution. The resulting reaction mixture was stirred for 3 h. The
aqueous phase was isolated and washed with chloroform. The
crude compound was purified by semi-preparative HPLC (tr =
32.3 min) to obtain 14 as a light-brown powder (5.0 mg,
0.010 mmol). The overall yield of the last three reactions was 12%.
1H NMR (300 MHz, D2O, 298 K): δ = 7.31 (s, 4 H, CHar), 4.05–
3.65 (m, 5 H), 3.58 (s, 2 H, PhCH2CO), 3.50–2.94 (m, 12 H), 2.91–
2.78 (m, 1 H), 2.75–2.61 (m, 1 H) ppm. MS (ESI): m/z = 507.98
[M + H]+. HRMS (ESI): calcd. for C22H29N5O7S + Na+ 530.1680
[M + Na]+; found 530.1687. C22H29N5O7S·CHCl3·2H2O (611.11):
calcd. C 41.67, H 5.17, N 10.56, S 4.84; found C 41.32, H 5.23, N
10.75, S 3.06. HPLC gradient: tr = 18.07 min, purity 90%.
Supporting Information (see footnote on the first page of this arti-
cle): Additional experimental details, data for compounds 1–15
(NMR, MS spectra, and HPLC chromatograms).
Acknowledgments
Financial support was provided by the Centre National de la Re-
cherche Scientifique (CNRS), the University of Burgundy and the
Conseil Régional de Bourgogne (3MIM project). Marie José Pen-
ouilh and Dr Fanny Picquet are acknowledged for technical sup-
port (NMR and mass spectrometric experiments).
[1] a) R. I. Haines, Rev. Inorg. Chem. 2001, 21, 165–205; b) K. P.
Wainwright, Coord. Chem. Rev. 1997, 166, 35–90.
[2] a) R. Hage, J. E. Iburg, J. Kerschner, J. H. Koek, E. L. M. Lem-
pers, R. J. Martens, U. S. Racherla, S. W. Russell, T. Swarthoff,
Nature 1994, 369, 637–639; b) R. Hage, D. Nuhlen, T. Weyher-
muller, K. Wieghardt, Unilever plc, WO 2001064826, 2001 (CA
2001:661544).
[3] a) N. Adams, H. J. Arts, P. D. Bolton, D. Cowell, S. R. Dubber-
ley, N. Friederichs, C. M. Grant, M. Kranenburg, A. J. Sealey,
B. Wang, P. J. Wilson, M. Zuideveld, A. J. Blake, M. Schroeder,
P. Mountford, Organometallics 2006, 25, 3888–3903; b) T.
Sakai, in: Olefin-Polymerizing Catalysts Containing Transition
Metal Complexes with Cyclic Amines, Japan Synthetic Rubber
Co., Ltd., Japan, EP0816387A1, 1998 (CA 1998:116104).
[4] V. C. Quee-Smith, L. DelPizzo, S. H. Jureller, J. L. Kerschner,
R. Hage, Inorg. Chem. 1996, 35, 6461–6465.
[5] D. De Vos, T. Bein, J. Am. Chem. Soc. 1997, 119, 9460–9465.
[6] a) B. C. Gilbert, J. R. Lindsay Smith, P. A. Mairata, J. Oakes,
P. R. Pons, J. Mol. Catal. A 2004, 219, 265–272; b) C. Han-
dervan, R. Ge, B. L. Feringa, Chem. Commun. 1997, 419–420.
[7] D. L. Johnson, L. L. Martin, J. Am. Chem. Soc. 2005, 127,
2018–2019.
[8] W. B. Tolman, Acc. Chem. Res. 1997, 30, 227–237.
[9] a) R. J. Parker, L. Spiccia, K. J. Berry, G. D. Fallon, B. Mouba-
raki, K. S. Murray, Chem. Commun. 2001, 333–334; b) J. J. So-
kol, A. G. Hee, J. R. Long, J. Am. Chem. Soc. 2002, 124, 7656–
7657.
[10] a) R. E. Mewis, S. J. Archibald, Coord. Chem. Rev. 2010, 254,
1686–1712; b) F. Liang, S. H. Wan, Z. Li, X. Q. Xiong, L.
Yang, X. Zhou, C. T. Wu, Curr. Med. Chem. 2006, 13, 711–
727; c) S. Dissoki, A. Hagooly, S. Elmachily, E. Mishani, J.
Labelled Compd. Radiopharm. 2011, 54, 693–701; d) G. Grif-
fiths, W. McBride, Immunomedics Inc (US) and McCALL
John, Douglas (GB), WO 03/059397 A2, 2003 (CA
2003:570856); e) K. Suzuki, N. Shimmura, K. Thipyapong, T.
Uehara, H. Akizawa, Y. Arano, Inorg. Chem. 2008, 47, 2593–
2600.
[11] a) K. P. Eisenwiener, M. I. Prata, I. Buschmann, H. W. Zhang,
A. C. Santos, S. Wenger, J. C. Reubi, H. R. Macke, Bioconjug-
ate Chem. 2002, 13, 530–541; b) B. M. Zeglis, J. S. Lewis, Dal-
ton Trans. 2011, 40, 6168–6195; c) C. Forster, M. Schubert,
H. J. Pietzsch, J. Steinbach, Molecules 2011, 16, 5228–5240; d)
L. Hoigebazar, J. M. Jeong, S. Y. Choi, J. Y. Choi, D. Shetty,
Y. S. Lee, D. S. Lee, J. K. Chung, M. C. Lee, Y. K. Chung, J.
Med. Chem. 2010, 53, 6378–6385.
N-[(1,4,7-Triazacyclononan-2-yl)methyl][4-(prop-2-ynyloxy)phen-
yl]methanamine (15): Compound 7 (1.20 g, 7.5 mmol) was added to
a solution of 4-(prop-2-ynyloxy)benzaldehyde (1.19 mg, 7.5 mmol)
in ethanol (25 mL) and the mixture stirred at room temperature for
48 h. The solvent was evaporated to dryness and the residual oil
was taken up in diethyl ether (25 mL). After stirring for 12 h, the
insoluble impurities were removed by filtration. After evaporation
of the solvent, NaBH4 (250 mg, 6.7 mmol) was added in ethanol
(10 mL) at 0 °C. The mixture was stirred overnight at room tem-
perature. The solvent was evaporated and the resulting solid was
dissolved in dichloromethane (25 mL). After filtration of the insol-
uble impurities, the solution was washed with 3 m NaOH (10 mL),
dried with MgSO4, and the solvent evaporated to give 15 as a very
hygroscopic white foam (135 mg, 68%). 1H NMR (300 MHz,
3
3
CDCl3, 298 K): δ = 7.18 (d, JH,H = 8.7 Hz, 2 H), 6.86 (d, JH,H
=
8.7 Hz, 2 H), 4.61 (d, 4JH,H = 2.3 Hz, 2 H, CH2CCH), 3.65 (s, 2 H),
2.90–2.30 (m, 15 H), 1.60–1.10 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3, 298 K): δ = 156.6, 130.1, 129.3 (2 C), 114.8 (2 C), 78.8
(CH2CCH), 75.6 (CH2CCH), 55.9, 55.6, 53.6, 49.9, 47.3, 47.2, 47.0,
46.4, 46.0 ppm. MS (ESI): m/z = 303.22 [M + H]+.
Crystal data for 2: C27H41Cl2N3O3, M = 526.53, monoclinic,
P21/c, a = 9.513(5), b = 34.739(5), c = 9.870(4) Å, β = 120.73(4)°,
V = 2804(2) Å3, Z = 4, T = 115(2) K, Dc = 1.247 gcm–3, (Mo-
K
α1) = 0.71073 Å, μ = 0.264 mm–1, 12685 reflections collected, 6437
unique, minimum and maximum residual electron densities: –0.601
and 0.528 eÅ–3. For IϾ2σ(I) and all data, R(1) = 0.0523 and
0.1035, and wR(2) = 0.1368 and 0.1561 , respectively.
¯
Crystal Data for 6: C28H44Cl4N4O2, M = 610.47, triclinic, P1, a =
9.1187(2), b = 12.0008(2), c = 15.4937(3) Å, α = 70.1260(10), β =
86.6110(10), γ = 86.2630(10)°, V = 1589.90(5) Å3, Z = 2, T =
115(2) K, Dc
= ) = 0.71073 Å, μ =
1.275 gcm–3, (Mo-Kα1
0.403 mm–1, 11218 reflections collected, 7195 unique, minimum
and maximum residual electron densities: –0.761 and 0.938 eÅ–3.
For IϾ2σ(I) and all data, R(1) = 0.0501 and 0.0630, and wR(2) =
0.1456 and 0.1553, respectively.
Crystal Data for 7: C7H24Cl4N4O, M = 322.10, monoclinic, P21/c,
a = 10.8478(3), b = 6.9249(2), c = 19.6388(7) Å, β = 102.912(2)°,
V = 1437.96(8) Å3, Z = 4, T = 115(2) K, Dc = 1.488 gcm–3, (Mo-
[12] a) J. Notni, P. Hermann, J. Havlickova, J. Kotek, V. Kubicek,
J. Plutnar, N. Loktionova, P. J. Riss, F. Rosch, I. Lukes, Chem.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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F. Denat et al.
FULL PAPER
Eur. J. 2010, 16, 7174–7185; b) J. Simecek, O. Zemek, P. Her-
mann, H.-J. Wester, J. Notni, ChemMedChem 2012, 7, 1375–
1378; c) X. Chen, Z. Li, Univ. Stanford, US, 2008/0267882,
2008 (CA 2008:1310264).
[15]
[16]
J. H. Koek, E. W. J. M. Kohlen, Tetrahedron Lett. 2006, 47,
3673–3675.
F. Denat, Y. Rousselin, P. Désogère, F. Boschetti, C. Bernhard,
Université de Bourgogne, CNRS, WO2014079953 (A1),
US2014142298, FR2998298, 2012 (CA 2014:830868).
O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard,
H. Puschmann, J. Appl. Crystallogr. 2009, 42, 339.
[13] a) J. E. Richman, T. J. Atkins, J. Am. Chem. Soc. 1974, 96,
2268–2270; b) R. C. Hoye, J. E. Richman, G. A. Dantas, M. F.
Lightbourne, L. S. Shinneman, J. Org. Chem. 2001, 66, 2722–
2725.
[17]
[18] Y. Rousselin, N. Sok, F. Boschetti, R. Guilard, F. Denat, Eur.
J. Org. Chem. 2010, 1688–1693.
[19] a) T. Mindt, C. Muller, F. Stuker, J. F. Salazar, A. Hohn, T.
Mueggler, M. Rudin, R. Schibli, Bioconjugate Chem. 2009, 20,
1940–1949; b) M. E. Martin, S. G. Parameswarappa, M. S.
O’Dorisio, F. C. Pigge, M. K. Schultz, Bioorg. Med. Chem.
Lett. 2010, 20, 4805–4807.
[14] a) A. S. Craig, I. M. Helps, K. J. Jankowski, D. Parker,
N. R. A. Beeley, B. A. Boyce, M. A. W. Eaton, A. T. Millican,
K. Millar, A. Phipps, S. K. Rhind, A. Harrison, C. Walker, J.
Chem. Soc., Chem. Commun. 1989, 794–796; b) J. E. W.
Scheuermann, K. F. Sibbons, D. M. Benoit, M. Motevalli, M.
Watkinson, Org. Biomol. Chem. 2004, 2, 2664–2670; c) G. Arg-
ouarch, C. L. Gibson, G. Stones, D. C. Sherrington, Tetrahe-
dron Lett. 2002, 43, 3795–3798; d) G. Argouarch, G. Stones,
C. L. Gibson, A. R. Kennedy, D. C. Sherrington, Org. Biomol.
Chem. 2003, 1, 4408–4417; e) G. Stones, G. Argouarch, A. R.
Kennedy, D. C. Sherrington, C. L. Gibson, Org. Biomol. Chem.
2003, 1, 2357–2363.
[20] M. Pal, K. Parasuraman, K. R. Yeleswarapu, Org. Lett. 2003,
5, 349–352.
Received: June 6, 2014
Published Online: ᭿
8
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Date: 03-09-14 19:51:35
Pages: 9
Triazacyclononane-Based Bifunctional Chelators
Chelators for Bioconjugation
P. Désogère, Y. Rousselin, S. Poty,
C. Bernhard, C. Goze, F. Boschetti,
F. Denat* .......................................... 1–9
Efficient Synthesis of 1,4,7-Triazacyclo-
nonane and 1,4,7-Triazacyclononane-
Based Bifunctional Chelators for Biocon-
jugation
A new synthesis of 1,4,7-triazacyclononane
and its N-functionalized derivatives is de-
scribed. This powerful approach outper-
forms previous synthetic methods due to
the use of an aminal intermediate. The
method can be extended to the synthesis of
valuable C-functionalized building blocks,
giving access to a wide range of new bi-
functional chelating agents, such as the p-
NCS-Bz-MA-NOTA chelator.
Keywords: Synthetic methods / Nitrogen
heterocycles / Amines / Macrocyclic poly-
amines / Chelates
Eur. J. Org. Chem. 0000, 0–0
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